Lung cancer is the leading cause of cancer deaths in the United States, of which 80% are non-small cell lung cancer (NSCLC). Although surgery provides the best chance of cure, the majority of NSCLC require radiation for treatment. The current radiation regimen, using modern techniques and a uniform dose of prescription, generates an overall cure rate of less than 10-15%, and moderate toxicity in 10-30% of treated patients. Who can be cured and who will develop side effects? Computed tomography (CT) provides a useful tool to monitor, but a limited power to predict both tumor control and lung toxicity. Using [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) and ventilation/perfusion single photon emission computed tomography (V/Q SPECT), we have recently demonstrated a heterogeneous change in tumor activity and regional lung function during the course of radiation, which may be associated with long-term outcome. We has also shown that radiation up- regulates the expression of cytokines such as transforming growth factor beta 1 (TGF_1) and interleukin-6 (IL-6), which is associated with lung toxicity. We hypothesize that the radiation-induced changes in tumor metabolic activity and lung functional mapping as well as plasma cytokines are associated with long- term tumor control and radiation lung damage. The general strategy of this project is to perform PET, SPECT and blood test during the course of radiation and correlate them with long-term outcomes. The specific aims of this study are to: 1) quantify changes in tumor FDG activity after 45Gy as measured by PET and examine their capability to predict long-term tumor control; 2) map the lung function and its changes on V/Q SPECT and assay plasma cytokines, such as TGF-_1 and IL-6 after 45Gy and determine their capability to predict radiation induced lung damage such as pulmonary function reduction and radiation pneumonitis and fibrosis. By completing this study, we expect to generate predictive models better than CT based ones for both tumor control and lung toxicity. Our long-term goal is to develop a strategy to tailor the therapy of each individual patient for a maximized therapeutic gain by escalating the dose of radiation to tumors of low probability of control and taking preventive measures in patients at high risk for lung toxicity. Lung cancer is the leading cause of cancer death in the United States and worldwide. Majority of lung cancer patients require radiation as part of their treatment. Despite advances in radiation technology, treatment outcomes remain poor, with an overall cure rate of less than 10-15% and moderate toxicity in 10-30% of treated patients. At this time, there is no reliable way to predict which patient will have the cancer controlled and which patient will develop toxicity as a result of receiving a particular dose of radiation therapy to treat their lung cancer. In the proposed clinical trial, we will enroll patients who have been diagnosed with non-small-cell lung cancers and are planning to receive radiation therapy as a part of their treatment. At midway during their course of radiation treatments, each patient will undergo PET/CT scan for measuring tumor activity/size and V/Q SPECT scan for mapping lung function. At three points during their course of radiation treatments, each patient will have blood drawn for markers. The results of these tests will be analyzed to determine their ability to accurately predict both the chance of long-term tumor control and the risk for developing lung toxicity. If successful, future radiation therapy could be personalized based on their response to radiation and treatment gain could be maximized. [unreadable] [unreadable] [unreadable]